Abstract The prevalence of cigarette smoking among American Indians (AIs) is disturbingly high, and only made worse by a high level of polytobacco use. Although the factors that mediate tobacco use are complex, it is clear that nicotine plays a vital role. Understanding how the addictive drug nicotine is contributing to this vulnerability among AIs is critically important to significantly reduce their disproportionately high smoking rate. The rate at which nicotine is metabolized is one of the most important predictors of smoking behavior and dependence. Nicotine metabolism has been shown to vary by race; these differences are hypothesized to result in racial disparities in exposure to tobacco-related toxicants and tobacco-related disease risk. To date, there is only one unpublished study of nicotine metabolism among AI tobacco users. Moreover, nicotine metabolism has not been measured among electronic cigarette (e-cigarette) users or polytobacco users of any kind, two classes of nicotine users that are prevalent within the AI population. To begin to fill this knowledge gap, we propose a study with the following aims: Aim 1: To estimate nicotine metabolism among exclusive cigarette smokers, exclusive e-cigarette users and exclusive dual cigarette/e-cigarette users of AI descent and conduct comparisons to previously characterized races, and Aim 2: To evaluate the effect of variation in nicotine metabolism on biomarkers of nicotine and carcinogen exposure in exclusive cigarette smokers, exclusive e- cigarette users and dual users of AI descent. Ninety adults of AI descent from Southern Plains tribes will be recruited into one of the following categories: 1) current exclusive cigarette smokers (n=30), 2) current exclusive e-cigarette users (n=30), and 3) dual users (n=30). All participants will have used cigarettes and/or e- cigarettes ad libitum in the 24-hour period prior to the study. Participants will provide a single urine sample, which will be analyzed for a validated biomarker for nicotine metabolism, as well as biomarkers for nicotine and carcinogen exposure. Participants will complete a questionnaire assessing socio-demographic characteristics, lifestyle behaviors, tobacco/e-cigarette use history, and nicotine dependence, as well as provide a measurement of carbon monoxide in exhaled breath. Estimating nicotine metabolism among AI cigarette smokers, e-cigarette users, and dual cigarette/e-cigarette users and its effect on users' exposure to tobacco- related toxicants is critically important and will have implications for not only cessation interventions but for regulatory authorities that are actively trying to understand the impact of e-cigarettes on the public health in general and disparate populations.